The goal of this mentored Career Development Award is to facilitate the primary investigator's transition to independence as a physician-scientist studying the molecular mechanisms of neurodegeneration. The proposed research, which will be conducted under the mentorship of Dr. David Holtzman, will examine the potential role of circadian clock genes as master regulators of neuronal oxidative stress and metabolism, and examine the role of the circadian clock in neurodegeneration. Circadian dysfunction is a prominent symptom of many age-related neurodegenerative diseases, including Alzheimer's disease. However, the impact of circadian dysfunction on neurodegenerative disease pathogenesis, if any, is unknown. On a molecular level, circadian rhythms are generated by conserved transcriptional machinery (the core circadian clock) that is present in most cells in the body, including neurons and glia, and oscillates with a 24 hour periodicity. In many tissues, circadian clocks serve as master regulators of metabolism, aging, and oxidative stress, though this has not been demonstrated in the brain. The goal of this project is to test the hypothesis that circadian clock dysfunction contributes to the pathogenesis of neurodegenerative diseases, in particular Alzheimer's disease. In order to test this hypothesis, the effect of genetic deletionof the master circadian clock gene Bmal1 on brain function and pathology will be examined through the following aims: 1) Elucidation of neuropathology changes in Bmal1 knockout mice, and identification of specific signaling abnormalities in clock-regulated pathways which mediate these changes. 2) Examination of the effect of Bmal1 deletion on neuronal metabolism, oxidative stress, and amyloid-beta regulation in living mice using in vivo micro dialysis. 3) Determination of the impact of brain-specific Bmal1 deletion on disease pathogenesis, oxidative stress, and amyloid-beta dynamics in a mouse model of Alzheimer's disease. The proposed experiments are designed to illuminate a possible novel link between circadian clock dysfunction and neurodegeneration, with the ultimate goal of indentifying novel therapeutic targets for age-related neurodegenerative conditions. This training grant will provide the primary investigator with research training which will parallels his clinical focus in dementia, and will ultimately provide a skill set for translation of basic science discoveries into diagnostic and therapeutic strategies for patients with neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: Neurodegenerative diseases, including Alzheimer's disease, afflict tens of millions of people worldwide and are increasingly critical public health problems. Circadian rhythm abnormalities are important symptoms of many of these diseases, but the impact of abnormal circadian function on the occurrence and progression of these diseases in unknown. An understanding of how abnormal circadian rhythms may predispose the brain to neurodegenerative illnesses could lead to new therapies for these devastating diseases.